Since the isolation of an active antibiotic from the mold Cephalosporium acremonium and the identification of the chemical structure of its nucleus, 7-aminocephalo-sporanic acid, a profusion of cephalosporins has been synthesized. Like penicillins, the cephalosporins owe their antibacterial activity to the presence of the .beta.-lactam ring. Some cephalosporins exhibit a broad range of anti-bacterial activity, including activity against organisms, notably staphylococci, which are resistant to penicillins. Much of the broader range of activity shown by these cephalosporins over penicillins may be attributed to their resistance to a large number of .beta.-lactamases which inactivate penicillins.
Both penicillins and cephalosporins may be administered parenterally. However, some penicillins, notably, phenoxy penicillin, indanyl carbenicillin, inter alia, may also be administered orally. However, by comparison, only a few cephalosporins may be administered orally. Moreover, despite considerable efforts directed toward finding side chains that will impart oral absorbability in cephalosporins, e.g., by analogy to penicillins, only D-(-)-arylglycyl- or dihydrophenylglycyl-substituted cephalosporins possess significant oral absorption. Chemistry and Biology of .beta.-Lactam Antibiotics, 1: 391 (Robert B. Morin and Marvin Gorman, eds., 1982). Indeed, it has been opined that the synthesis of a cephalosporin with both broad spectrum antimicrobial activity and the capability of being orally absorbed will be fortuitous. Id. at 397.
The "prodrug" concept has been employed for both penicillins and cephalosporins; i.e., the administration of an inactive substance, such as an ester, which is metabolized by the body to an active component, e.g., the free acid. For penicillins, several esters have been synthesized which will be metabolized to active antibiotics. Among such esters are pivaloyloxymethyl, methoxymethyl and indanyl. However, the prodrug concept has not been as sucessful with cephalosporins. Chemistry and Biology of .beta.-Lactam Antibiotics, 1: 404. Moreover, it is believed that with regard to cephalosporins in particular, whether an ester will render any given cephalosporin orally absorbable cannot be predicted. Drugs of Today, 19: 499-538 (1983). It has been opined that a general problem inherent with all cephalosporin esters may be the great propensity for these derivatives to give rise to a mixture of .DELTA..sup.2 and .DELTA..sup.3 isomers in vivo, the .DELTA..sup.2 isomers being inactive. Id. at 528.
In European Patent Application No. 81304416.1, the above-stated problems of obtaining an orally active, broad-spectrum cephalosporin are described. As noted therein, it has been difficult synthesizing a cephalosporin with a broad-spectrum of activity which (i) can be esterified to a prodrug and (ii) retains its activity upon metabolism. Specifically, such application discloses that certain 7-aminothiazole alkoxy-imino-acetamido cephalosporins either form orally inactive esters or esters with reduced spectrum of activity. In particular, the application discloses that such cephalosporins having at the 3-position a thiadiazolyl-thiomethyl have not been shown to form esters effective as prodrugs.